Akt Inhibitor Perifosine Prevents Epileptogenesis in a Rat Model of Temporal Lobe Epilepsy
Akt Inhibitor Perifosine Prevents Epileptogenesis in a Rat Model of Temporal Lobe Epilepsy
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Akt 抑制剂哌立福辛可预防颞叶癫痫大鼠模型中的癫痫发生
DOI：
10.1007/s12264-017-0165-7
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Ling—Hui Zeng
中科院分区：
文献类型：
--
作者：
Feng Zhu;Jiejing Kai;Linglin Chen;Meiling Wu;Jingyin Dong;Wingmei Wang;Ling—Hui Zeng
越来越多的数据表明，mTOR（哺乳动物雷帕霉素靶蛋白）通路的异常活性在多种因素引发的癫痫发生中起着重要作用。我们之前报道过，在kainic酸（KA）诱导的大鼠模型中，用perifosine （Akt的抑制剂，也称为蛋白激酶B）预处理，可以消除雷帕霉素诱导的S6磷酸化的矛盾增加。由于Akt是mTOR信号通路的上游靶点，我们开始确定perifosine是否对癫痫发生具有预防作用。在此，我们探讨了紫花碱对KA诱导的大鼠颞叶癫痫模型的影响，发现紫花碱预处理对KA诱导的癫痫持续状态的严重程度和持续时间没有影响。然而，在ka诱导的癫痫持续状态后，perifosine几乎完全抑制了p-Akt和p-S6的急性和慢性激活。滨草碱预处理对ka诱导的神经元死亡和苔藓纤维萌发有抑制作用。经紫花苜蓿预处理的大鼠自发性癫痫发作频率明显降低。因此，经紫苏碱预处理的大鼠认知功能出现轻度损伤。总的来说，这项研究为KA癫痫发作模型提供了新的证据，表明perifosine可能是一种潜在的抗癫痫治疗药物。
Accumulating data have revealed that abnormal activity of the mTOR (mammalian target of rapamycin) pathway plays an important role in epileptogenesis triggered by various factors. We previously reported that pretreatment with perifosine, an inhibitor of Akt (also called protein kinase B), abolishes the rapamycin-induced paradoxical increase of S6 phosphorylation in a rat model induced by kainic acid (KA). Since Akt is an upstream target in the mTOR signaling pathway, we set out to determine whether perifosine has a preventive effect on epileptogenesis. Here, we explored the effect of perifosine on the model of temporal epilepsy induced by KA in rats and found that pretreatment with perifosine had no effect on the severity or duration of the KA-induced status epilepticus. However, perifosine almost completely inhibited the activation of p-Akt and p-S6 both acutely and chronically following the KA-induced status epilepticus. Perifosine pretreatment suppressed the KA-induced neuronal death and mossy fiber sprouting. The frequency of spontaneous seizures was markedly decreased in rats pretreated with perifosine. Accordingly, rats pretreated with perifosine showed mild impairment in cognitive functions. Collectively, this study provides novel evidence in a KA seizure model that perifosine may be a potential drug for use in anti-epileptogenic therapy.
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作者：
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